In the complex landscape of melanoma treatment, especially in advanced stages, systemic therapy remains the cornerstone approach. When surgical options are no longer viable due to the extent of disease spread, systemic treatments provide vital hope and control. The decision to pursue systemic therapy depends on multiple factors, including patient health status, disease progression speed, metastatic sites and burden, genetic mutations within the tumor, and patient preferences. These therapies encompass various modalities, mainly categorized into cytotoxic chemotherapy, targeted molecular therapies, and immunotherapy, each playing a pivotal role in managing metastatic melanoma.

Over the past thirty years, cytotoxic chemotherapy has been a foundational treatment for metastatic melanoma. Although its efficacy varies, chemotherapy agents are designed to directly target and kill rapidly dividing cancer cells. Despite modest success, they provide an option for some patients, especially when other therapies are unsuitable. Immunotherapy, another critical systemic approach, has revolutionized melanoma treatment. It enhances the body’s immune response against tumor cells, offering improved survival outcomes, particularly in high-risk metastatic cases. The U.S. Food and Drug Administration (FDA) has approved several immunotherapies for melanoma, including T-VEC (talimogene laherparepvec), nivolumab (Opdivo), pembrolizumab (Keytruda), a combination of ipilimumab (Yervoy) and nivolumab, ipilimumab alone, interleukin-2 (IL-2), and interferon alpha 2-b.

Immunotherapy operates by stimulating or restoring the immune system's ability to recognize and attack cancer cells. Given that melanoma is highly immunogenic, harnessing the body's immune defenses can be highly effective in controlling disease progression. Currently, immunotherapy has become a preferred treatment due to its potential for durable responses. Researchers are continuously developing new immunotherapeutic approaches, including combination therapies and novel agents, which are expected to further improve outcomes for patients with metastatic melanoma in the near future.